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Monoclonal antibodies for malaria prevention.

ABSTRACT: Monoclonal antibodies are highly specific proteins that are cloned from a single B cell and bind to a single epitope on a pathogen. These laboratory-made molecules can serve as prophylactics or therapeutics for infectious diseases and have an impressive capacity to modulate the progression of disease, as demonstrated for the first time on a large scale during the COVID-19 pandemic. The high specificity and natural starting point of monoclonal antibodies afford an encouraging safety profile, yet the high cost of production remains a major limitation to their widespread use. While a monoclonal antibody approach to abrogating malaria infection is not yet available, the unique life cycle of the malaria parasite affords many opportunities for such proteins to act, and preliminary research into the efficacy of monoclonal antibodies in preventing malaria infection, disease, and transmission is encouraging. This review examines the current status and future outlook for monoclonal antibodies against malaria in the context of the complex life cycle and varied antigenic targets expressed in the human and mosquito hosts, and provides insight into the strengths and limitations of this approach to curtailing one of humanity's oldest and deadliest diseases.

SUBMITTER: Aleshnick M

PROVIDER: S-EPMC8979832 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Monoclonal antibodies for malaria prevention.

Aleshnick Maya M Florez-Cuadros Melina M Martinson Thomas T Wilder Brandon K BK

Molecular therapy : the journal of the American Society of Gene Therapy 20220405 5

Monoclonal antibodies are highly specific proteins that are cloned from a single B cell and bind to a single epitope on a pathogen. These laboratory-made molecules can serve as prophylactics or therapeutics for infectious diseases and have an impressive capacity to modulate the progression of disease, as demonstrated for the first time on a large scale during the COVID-19 pandemic. The high specificity and natural starting point of monoclonal antibodies afford an encouraging safety profile, yet ...[more]

PMID: 35395399

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Project description:BackgroundAdditional interventions are needed to reduce the morbidity and mortality caused by malaria.MethodsWe conducted a two-part, phase 1 clinical trial to assess the safety and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an extended half-life, and its efficacy against infection with Plasmodium falciparum. Part A of the trial assessed the safety, initial side-effect profile, and pharmacokinetics of CIS43LS in healthy adults who had never had malaria. Participants received CIS43LS subcutaneously or intravenously at one of three escalating dose levels. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS infusion. Additional participants were enrolled in Part B and received CIS43LS intravenously. To assess the protective efficacy of CIS43LS, some participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying P. falciparum sporozoites 4 to 36 weeks after administration of CIS43LS.ResultsA total of 25 participants received CIS43LS at a dose of 5 mg per kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the 25 participants received a second dose (20 mg per kilogram regardless of initial dose). No safety concerns were identified. We observed dose-dependent increases in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9 participants who received CIS43LS, as compared with 5 of 6 control participants who did not receive CIS43LS, had parasitemia according to polymerase-chain-reaction testing through 21 days after controlled human malaria infection. Two participants who received 40 mg per kilogram of CIS43LS and underwent controlled human malaria infection approximately 36 weeks later had no parasitemia, with serum concentrations of CIS43LS of 46 and 57 μg per milliliter at the time of controlled human malaria infection.ConclusionsAmong adults who had never had malaria infection or vaccination, administration of the long-acting monoclonal antibody CIS43LS prevented malaria after controlled infection. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.).

Project description:IntroductionThe last 12 years have seen remarkable progress in the isolation and characterization of at least five different epitope classes of HIV-specific broadly neutralizing antibodies (bnAbs). Detailed analyses of these bnAb lineages, maturation pathways and epitopes have created new opportunities for vaccine development. In addition, interest exists in passive administration of monoclonal antibodies as a viable option for HIV prevention.DiscussionRecently, two antibody-mediated prevention (AMP) trials of a passively administered monoclonal antibody targeting the HIV envelope CD4 binding site, called VRC01, provided proof-of-concept that monoclonal antibody infusion could offer protection against HIV acquisition. While the trials failed to show overall protection against HIV acquisition, sub-analyses revealed that VRC01 infusion provided a 75% prevention efficacy against HIV strains that were susceptible to the antibody. The study also demonstrated that in vitro neutralizing activity, measured by the TZM-bl/pseudovirus assay, was able to predict HIV prevention efficacy in humans. In addition, the AMP trials defined a threshold protective concentration, or neutralization titer, for the VRC01 class of bnAbs, explaining the observed low overall efficacy and serving as a benchmark for the clinical testing of new bnAbs, bnAb cocktails and neutralizing antibody-inducing vaccines. Newer bnAbs that exhibit greater potency and breadth of neutralization in vitro than VRC01 are available for clinical testing. Combinations of best-in-class bnAbs with complementary magnitude, breadth and extent of complete neutralization are predicted to far exceed the prevention efficacy of VRC01. Some engineered bi- and trispecific mAbs exhibit similar desirable neutralizing activity and afford advantages for manufacturing and delivery. Modifications that prolong the serum half-life and improve genital tissue persistence offer additional advantages.ConclusionsIterative phase 1 trials are acquiring safety and pharmacokinetic data on dual and triple bnAbs and bi- and trispecific antibodies in preparation for future AMP studies that seek to translate findings from the VRC01 efficacy trials and achieve acceptable levels of overall prevention efficacy.

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Monoclonal antibodies for malaria prevention.

Publications

Monoclonal antibodies for malaria prevention.

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